DESCRIPTION: With 35 million HIV-infected individuals worldwide, the challenge to improve health in these individuals is vast. Antiretroviral therapy (ART) suppresses HIV replication, which prevents AIDS and reduces overall mortality; however ART does not fully restore health. Indeed, despite sustained suppression of viremia, individuals cannot discontinue ART as residual HIV persists, and virus rebound is inevitable if ART is discontinued. This residual HIV reservoir is associated with ongoing inflammation. Cannabis is a widely used drug in the United States, and derivatives of cannabis such as cannabinoids are commonly used in treatment of nausea and cachexia in severe conditions such as cancer. Several studies have demonstrated that cannabinoids have the propensity to alter immune responses and decrease inflammation in vivo. We hypothesize that cannabis use in the context of ART-treated HIV infection may decrease inflammation and the persistent HIV reservoir. Here, we provocatively propose to test this hypothesis in humans by measuring inflammation, immunity, and the HIV reservoir from blood and gastrointestinal (GI) tissues from HIV-infected individuals who report using cannabis daily compared to those reporting no drug use. Furthermore, we will assess mechanisms of cannabinoid anti- inflammatory activity ex-vivo using cannabinoid receptor agonists in co-cultures. In addition, we will exploit the non-human primate model of SIV infection to test causality of this unconventional idea, by treating ART- treated, SIV infected macaques with cannabinoids to assess the effects on SIV reservoir and inflammation. With an outstanding team of researchers, we will assess the following: (i.) Global systems biology, including species-specific transcriptional analysis and bioinformatics; (ii.) The HIV and SIV reservoir using novel assays to measure integrated, total and inducible virus; (iii.) Inflammation and immunophenotype of immune cell subsets; (iv.) Systemic microbial translocation and GI tract barrier integrity; and (v.) drug levels and kinetics in blood and GI tract. We believe these proposed studies will be integral to better understanding facets associated with the HIV reservoir and may provide a novel therapeutic approach, exploiting a drug of abuse, towards development of an HIV cure.